Several publications and patent documents are referenced in this application in order to more fully describe the state of the art to which this invention pertains. The disclosure of each of these publications and documents is incorporated by reference herein in its entirety.
In general, the invention relates to methods for treating a neurological disease. Neurological diseases/disorders often progress rapidly and can be disruptive of essentially all aspects of a patient's life. As such, these diseases present profound challenges for the patient, care givers, and attending physicians. Moreover, the progressive nature of these diseases makes the passage of time a crucial consideration in the treatment process. Treatment choices for neurological diseases, particularly those affecting cognitive function, can be complicated by the duration of time which is frequently required to determine the efficacy of a therapeutic regimen. Indeed, depending on the disease involved, a significant percent of the population of affected individuals can present with a form of intractable disease.
Methodology directed to human gene therapy renders feasible the treatment of numerous neurological disorders via delivery of nucleic acid sequences directly to the nervous system, wherein their expression can be manipulated in a therapeutically beneficial manner. This is a particularly valuable option for patients with intractable neurological disease, who may, for example, have a form of the disease that is not responsive to the available drugs or may not be able to tolerate the deleterious side effects associated with many therapeutic modalities. Gene transfer into the central nervous system (CNS) is, however, impeded by several features of the system, including the largely post-mitotic nature of most neurons in the brain, constraints related to accessibility into various brain regions, and obstacles pertaining to the blood-brain-barrier.
Retroviral vectors, which are routinely used for somatic cell gene transfer, are not generally useful for applications in post-mitotic neural cells because retrovirally mediated gene transfer requires at least one cell division for integration and expression. To address the challenges inherent to gene transfer into the CNS, a number of vectors and non-viral methods have been developed. A number of studies have achieved varying degrees of success for gene transfer into the CNS using either an ex vivo approach, involving transplantation of cells retrovirally-transduced in vitro, or an in vivo approach. Investigators have also utilized HSV-1 and adenoviral vectors, as well as non-viral methods including cationic lipid mediated transfection to achieve gene transfer into cells of the CNS (Wolff (1993) Curr. Opin. Biol. 3:743-748).
Groves et al., for example, used an ex vivo approach to infect oligodendrocytes with retroviral vectors, which were subsequently transplanted into a syngeneic rat model for a demyelinating disorder (Groves et al (1993) Nature 362:453-457). Non-neuronal cells, including fibroblasts and primary muscle cells, have also been used successfully to introduce exogenous nucleic acid sequences and their encoded products into the CNS (Horrelou et al (1990) Neuron 5:393-402; Jiao et al (1993) Nature 362:450-453).
In vivo approaches have been largely directed to the use of the neurotropic Herpes Simplex Virus (HSV-1) and a number of adenoviral vectors, which have been shown to drive persistent expression (i.e., two months) of marker genes in the rat brain (Davidson et al (1993) Nature Genetics 3:219-2223). In addition to viral vector approaches, other investigators have used direct injection of a cationic liposome:plasmid complex and have demonstrated low level and transient expression of a marker gene using this approach (Ono et al (1990) Neurosci. Lett. 117:259-263).
There have, however, been very few studies directed to introducing “therapeutic” genes into cells of the CNS. The majority of these studies used an ex vivo approach involving transduction of fibroblasts and muscle cells with the human tyrosine hydroxylase gene, which provided a source of L-dopa-secreting cells for use in models of Parkinson's Disease (e.g., Horrelou et al (1990) Neuron 5:393-402; Jiao et al (1993) Nature 362:450-453). HSV vectors have been used for a number of ill vivo approaches involving expression of β-glucuronidase (Wolfe et al (1992) Nature Genetics 1:379-384), glucose transporter (Ho et al (1993) Proc. Natl. Acad. Sci. 90:6791-6795) and nerve growth factor (Federoff et al (1992) Proc. Natl. Acad. Sci. 89:1636-1640). An adenoviral vector has also been used successfully to induce low level transient expression of human α1-antitrypsin (Bajoccchi et al (1993) 3:229-234).
Very few clinical studies documenting gene transfer into the brain have been reported. Of these, Culver et al. [(1992) Science 256:18550-18522] essentially cured rats following the intracerebral implantation of glioma cell lines infected with a retrovirus expressing the HSV-1 thymidine kinase (tk) gene, which were subsequently treated with ganciclovir. The success achieved in the animal model led to approval of a human protocol for glioblastoma multiforme using the retroviral tk vector—ganciclovir approach (Oldfield et al (1993) Human Gene Ther. 4:39-69).